Rhodium-Promoted C–H Bond Activation of Quinoline, Methylquinolines, and Related Mono-Substituted Quinolines

The C–H bond activation of methylquinolines, quinoline, 3-methoxyquinoline, and 3-(trifluoromethyl)quinoline promoted by the square-planar rhodium(I) complex RhH{κ3-P,O,P-[xant(PiPr2)2]} [1; xant(PiPr2)2 = 9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene] has been systematically studied. Results reveal that the activation of the heteroring is preferred over the activation of the carbocycle, and the activated position depends upon the position of the substituent in the substrate. Thus, 3-, 4-, and 5-methylquinoline reacts with 1 to quantitatively form square-planar rhodium(I)-(2-quinolinyl) derivatives, whereas 2-, 6-, and 7-methylquinoline quantitatively leads to rhodium(I)-(4-quinolinyl) species. By contrast, quinoline and 8-methylquinoline afford mixtures of the respective rhodium(I)-(2-quinolinyl) and -(4-quinolinyl) complexes. 3-Methoxyquinoline displays the same behavior as that of 3-methylquinoline, while 3-(trifluoromethyl)quinoline yields a mixture of rhodium(I)-(2-quinolinyl), -(4-quinolinyl), -(6-quinolinyl), and -(7-quinolinyl) isomers.


■ INTRODUCTION
Direct C−H bond functionalization is a powerful and environmentally sustainable procedure, which converts simple compounds into valuable molecules, the C−H rupture being the key step in the processes of this class. 1 The strength of the different C−H bonds of an organic substrate is in a narrow range, as proven by their dissociation energies; the range is particularly narrow when the entire molecule is aromatic. Transition metal complexes display ability to modify in a different manner the activation energy of the rupture of the diverse aromatic C−H bonds, as a function of their position at the aromatic ring and of the electronic and steric properties of the substituents of such a ring. Accordingly, to selectively perform the cleavage of a particular C−H bond, a metal species is usually needed. 2 It is well established that the first step for a metal-promoted C−H bond rupture is the formation of a σintermediate L n M(η 2 -HC), which subsequently evolves by heterolytic or homolytic cleavage of the coordinated C−H bond. In this way, the activation energy of the rupture process is dependent on the stability of the σ-intermediate and the dissociation energy of the coordinated C−H bond. High chemo-and regioselectivities have been achieved by the kinetic governing of the rupture through the fine tuning of the electron density on the metal center and the design of the free space around the metal core, by choosing the ligands of the coordination sphere. 3 From a thermodynamic point of view, strengths of the possible M−C bonds in the product dominate the selectivity of the cleavage. 4 A quinoline core is present in many natural products and as a unit is a remarkable scaffold for the assembly of new pharmacological and agrochemical entities, given the diverse biological activity of this heterocycle and its derivatives. 5 Transition-metal-catalyzed C−H functionalization of quinolines is currently receiving great attention as an environmentally sustainable alternative to the classical functionalization procedures, which generate more wastes. 6 Functionalization of the C2 position is well established with a variety of transition-metal catalysts. 7 The functionalization of C3, 8 C4, 9 and C8 10 positions has been also achieved, although it is always a real challenge. On the other hand, selective functionalization of C5−C7 positions requires the help of an assistant on some ligand of the metal coordination sphere of the catalyst and/or at an adjacent position of the substrate. 11 The rationalization of these findings is certainly difficult, to a large extent due to the scarce number of systematic studies performed on the elemental reaction of metal-promoted C−H bond activation of quinolines. Such a stoichiometric process has been rarely observed at C2 and C8 positions. The activation of the C−H bond at the 2 position is facilitated by the proximity of the nitrogen atom, which many times acts as a coordination assistant, 12 whereas the rupture of the C−H bond at the 8 position takes place thanks to the formation of fivemembered metalacycles involving also the nitrogen. 13 Rhodium catalysts are among the most utilized for the functionalization of quinolines, in particular, to build C−C, C−N, and C−halogen bonds. 14 The square-planar monohydride complex RhH{κ 3 -P,O,P-[xant(P i Pr 2 ) 2 ]} [xant(P i Pr 2 ) 2 = 9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene] is a rare stable member of the family of late-transition metal unsaturated monohydride complexes, which was initially prepared in only moderate yield. 15 In spite of this unfortunate handicap, its chemistry was studied in some recent years, proving to promote the activation of a wide range of σbonds, 16 including C(sp 2 )−H bonds of arenes 17 and C(sp 3 )− H bonds of bis(alkyl)alkynes 18 to afford aryl and allyl derivatives (Scheme 1). In agreement with such ability, it was observed to be an efficient catalyst for C−H bond functionalization reactions such as the borylation of arenes 17 and the dehydrogenative borylation of bis(alkyl)alkynes. 18 Furthermore, it catalyzes the hydroboration of alkynes, 19 the deuteration of boranes and hydrides of group 14 elements, 20 the ammonia borane dehydrogenation, 21 and the dehydropolymerization of amine-boranes. 22 Two years ago, we improved significantly its synthesis, reducing the reaction time and increasing the yield, which now reaches 90%. 20 The interest in the rhodium catalysts in the C−H functionalization of quinolines, the enhancement of yield in the preparation of the monohydride RhH{κ 3 -P,O,P-[xant(P i Pr 2 ) 2 ]}, and its promising previous chemical behavior prompted us to employ this complex to perform a systematic study on the C−H bond activation of quinoline, its monomethyl-substituted counterparts, and related substituted quinolines. This paper reports the C−H bond activation of quinoline and substituted quinolines promoted by RhH{κ 3 -P,O,P-[xant(P i Pr 2 ) 2 ]}, demonstrates that the activated position depends upon the position of the substituent and its nature, presents the selective formation of the first-metal-(4quinolinyl) derivatives resulting from the direct C−H bond activation of a quinoline-type molecule, and reveals that the activation at 6 and 7 positions is also possible without the help of a coordination assistant. ■ RESULTS AND DISCUSSION C−H Bond Activation of Quinoline and Methylquinolines. In addition to quinoline, the substrates used were 2-, 3-, 4-, 5-, 6-, 7-, and 8-methylquinoline. The study was performed in n-octane, at 80°C, using 1:1 molar ratios of rhodium/ heterocycle. Reactions were followed by 31 P{ 1 H} NMR spectroscopy for 48−72 h, until quantitative transformation of rhodium(I)-hydride RhH{κ 3 -P,O,P-[xant(P i Pr 2 ) 2 ]} (1) into the corresponding rhodium(I)-quinolinyl reaction products. Such species, which are the first square-planar transition metal complexes bearing a quinolinyl ligand, result from the direct C−H bond activation of the substrate (HQ) and the subsequent fast elimination of molecular hydrogen (Scheme 2). Although the trans-disposition of the hydride ligands appears to be favored in the rhodium(III)-dihydride intermediates similarly generated from 1 in related processes, the reductive elimination of molecular hydrogen rapidly occurs in all the cases because the hemilabile character of the oxygen atom of the ether-diphosphine allows the necessary threecenter transition state. 16a, 17 The activated position depends on the position of the methyl substituent, with three different patterns of behavior being observed: selective activation of the C−H bond at position 2, selective activation of the C−H bond at position 4, and C−H bond activation competition between positions 2 and 4.
Selective Activation of the C−H Bond at Position 2. A methyl group at 3, 4, and 5 positions directs the C−H bond activation of the mono-substituted heterocycle to the 2 position. Thus, treatment of 1 with 3-, 4-, and 5-methylquinoline quantitatively leads to the rhodium(I)-(2-quinolinyl) derivatives 2−4 (Scheme 3), which were isolated as yellow solids in moderate yields, about 40%, due to their high solubility in alkanes including pentane.
The three compounds were characterized by X-ray diffraction analysis. Figure 1a−c gives views of the structures, which demonstrate the activation of the C−H bond at the 2 position and the square-planar environment of the rhodium atom with the ether-diphosphine mer-coordinated and the quinolinyl group trans-disposed to the oxygen atom. The Rh− C bond lengths are similar, being in the range 1.957(14)− 1.986(6) Å. It should be noted that unlike the previous cases involving activation of the C−H bond at position 2, 12f coordination of the N atom is not observed despite the formally unsaturated character of the metal center. This is not entirely surprising given the ability of d 8 ions to form squareplanar species of 16 valence electrons. The NMR spectra are consistent with the structures (Figures S2−S10). Aromatic hydrogen atoms give rise to the patterns expected for the corresponding substitutions of the heterocycles, in the 1 H spectra of the respective complexes ( Figures S3, S6, and S9). The resonance due to the metalated carbon atom is observed as a doublet of triplets ( 1 J C−Rh ≈ 43 Hz, 2 J C−P ≈ 11 Hz), between 197 and 200 ppm, in the 13 C{ 1 H} spectra, whereas the 31 P{ 1 H} spectra display a doublet ( 1 J P−Rh ≈ 185 Hz), close to 37 ppm, in agreement with the equivalence of the P i Pr 2 arms of the diphosphine.
Particularly noteworthy is the behavior of 3-methylquinoline. Such a substrate undergoes C−H bond activation in the heteroring in a sterically hindered position, adjacent to the methyl group, which makes it difficult for the C−H bond to approach the metal center. At first glance, this is surprising because the steric congestion around the carbocycle positions is significantly lower. On the other hand, it suggests that the activation of the heteroring positions is strongly favored with regard to those of the carbocycle for electronic reasons. The exclusivity in selection between positions 2 and 4 is also a remarkable finding as both are equally hampered by the methyl substituent.
Selective Activation of the C−H Bond at Position 4. A methyl group at 2, 6, and 7 positions of the mono-substituted quinoline directs the C−H bond activation to the 4 position, in contrast to the activations shown in Scheme 3. Thus, treatment of 1 with 2-, 6-, and 7-methylquinoline quantitatively affords the rhodium(I)-(4-quinolinyl) derivatives 5−7 (Scheme 4), which were isolated as yellow solids with yields from moderate to high (33−64%).
The formation of the first transition metal organometallic compounds resulting from the direct rupture of a C−H bond at the 4 position of a quinoline-type molecule was confirmed by the X-ray structures of 5 ( Figure 1d) and 6 ( Figure 1e). Both structures resemble those of 2−4 with Rh−C distances of 1.9692 (14) (5) and 1.9720(11) (6) Å. The NMR spectra of 5−7 also support the activation of the aromatic C−H bond at the 4 position of the quinoline, mainly the 1 H spectra (Figures S12, S15, and S18). Although the 13 C{ 1 H} and 31 P{ 1 H} spectra of these compounds and those of 2−4 are similar, there are between them enough differences to also convert these spectra into a characteristic feature of the activated position ( Table 1). The 13 C{ 1 H} spectra of 5−7 display the doublet of triplets ( 1 J C−Rh = 41−44 Hz, 2 J C−P = 10−12 Hz) due to the metalated carbon atom of the heterocycle at about 187 ppm, shifted around 10 ppm toward a higher field with regard to the complexes 2−4. In contrast, in the 31 P{ 1 H} spectra, the doublet generated by the equivalent P i Pr 2 arms of the diphosphine appears at about 38 ppm, slightly shifted to a lower field, with values for the P−Rh coupling constant close to 171 Hz, which are about 14 Hz smaller than those observed in 2−4.
Activation of the heteroring again was expected after observing the previous activations. However, the exclusive selection of the 4 position surprised us, given the activation of 3-methylquinoline at the 2 position and because the C−H bond at the 4 position is sterically more congested than those at 2 and 3 positions. One more time, steric reasons do not seem to be determinant in the C−H activation of these substrates. On the contrary, the substituent located in any position of both rings has a marked electronic repercussion in the activation of the C−H bonds of the heteroring; the activated C−H bond depends on the position of the methyl substituent, although the activation of the C−H bond in the 3 position seems hard to reach.
C−H Bond Activation Competition between Positions 2 and 4. In contrast to the previously mentioned heterocycles, quinoline and 8-methylquinoline undergo the rupture of the C−H bonds at 2 and 4 positions in a competitive manner, with the activation of the C−H bond at the 3 position being definitely elusive (Scheme 5). Treatment of 1 with quinoline under the standard conditions of the study gives rise to the formation of a yellow solid (51% yield) and an orange solution. The yellow solid was characterized as the rhodium(I)-(4quinolinyl) derivative 8, by X-ray diffraction analysis. Figure 1f shows its structure [Rh−C = 1.980(2) Å]. The solution contains a mixture of 8 and its 2-quinolinyl isomer 9 in a 3:7 molar ratio. The presence of the latter is strongly supported by the NMR spectra of the mixture ( Figures S23−S26). The 1 H spectrum shows the expected pattern for a Rh substitution at the 2 position of the heterocycle ( Figure S24), whereas the 13 C{ 1 H} spectrum contains a resonance at 196 ppm, and the 31 P{ 1 H} spectrum displays a doublet ( 1 J P−Rh = 184.7 Hz) at 37.7 ppm, in agreement with 2−4. The reaction of 1 with 8methylquinoline leads to a 1:1 mixture of the 4-quinolinyl derivative 10 and its 2-quinolinyl isomer 11. Orange single crystals of the latter, suitable for X-ray analysis, were isolated from the mixture. Figure 1g gives a view of the structure [Rh− C = 1.972(16) Å]. Complex 10 was fully characterized by NMR spectroscopy. The spectra show characteristic features of Rh(I)-(4-quinolinyl) complexes (Figures S27−S31). In accordance with 5−7, the 13 C{ 1 H} spectrum contains a doublet of triplets ( 1 J C−Rh = 41.5 Hz, 2 J C−P = 12.5 Hz) at 188.3 ppm, whereas the 31 P{ 1 H} spectrum displays a doublet ( 1 J P−Rh = 171.8 Hz) at 38.1 ppm.
The formation of 8−11 confirms that the C−H bond activation of quinoline can be selectively directed to the 2 or 4 position by the introduction of a methyl substituent at the appropriate place on the heterocycle, with the exception of the 8 position.
C−H Bond Activation of Related Mono-Substituted Quinolines. Having established that a methyl group, located at any position of the quinoline rings, directs the C−H bond activation of the corresponding heterocycle to 2 or 4 positions and upon observing a scarce steric influence of the methyl group on the process, in contrast to the C−H bond activation of aromatic hydrocarbons, 17,23 we decided to study the influence of markedly different substituents from an electronic point of view. We selected methoxide as a strongly electrondonating group, trifluoromethyl as a notable electron-withdrawing substituent, and the 3 position on being adjacent to both previously activated bonds. The methoxide group does not change the rate or the selectivity of the activation with regard to methyl. Treatment of 1 with 3-methoxyquinoline quantitatively leads to a 2quinolinyl derivative, 12 (Scheme 6), after 72 h as 3methylquinoline. Complex 12 was isolated as an orange solid and characterized by X-ray diffraction analysis. Figure 1h shows a view of the structure. The Rh−C bond length of 1.9678 (17) Å is statistically identical to that of the 3-methyl counterpart. The NMR spectra agree well with those of the 2quinolinyl derivatives 2−4, 9, and 11 ( Figures S32−S34). The 13 C{ 1 H} spectrum contains a doublet of triplets ( 1 J C−Rh = 45.1 Hz, 2 J C−P = 11. 2 Hz) in the expected region, 192.9 ppm, whereas the 31 P{ 1 H} spectrum shows a doublet at 38.6 ppm with a P−Rh coupling constant displaying a value of 183.0 Hz, which lies in the same range as those of 2−4, 9, and 11.
The trifluoromethyl group introduces very noticeable changes. It slows down the rate of the reaction and dramatically reduces the selectivity, promoting the activations of the C−H bonds at 2, 4, 6, and 7 positions (Scheme 7). Thus, the treatment of 1 with 3-(trifluoromethyl)quinoline gives a mixture of derivatives 13 (2-quinolinyl, 25%), 14 (4quinolinyl, 14%), 15 (6-quinolinyl, 25%), and 16 (7quinolinyl, 36%), after 5 days, according to the 31 P{ 1 H} NMR spectrum of the resulting solution in n-octane ( Figure  S35). The presence of 13 and 14 in the mixture is supported by the values of the P−Rh coupling constants obtained from the respective doublets at 35.3 and 37.5 ppm, of 183.9 and 174.6 Hz, which, respectively, lie in the range of the coupling constants observed in the previous 2-quinolinyl and 4quinolinyl complexes (see Table 1). The evaporation of noctane affords a reaction crude that when subsequently treated with pentane, yields a red solid only formed by 15 and 16 in a 1:2.5 molar ratio. Such a solid allowed us to obtain fine 1   crystals obtained from the original solution in n-octane. X-ray diffraction of an orange single crystal provided the structure of 13 (Figure 1i), which showed a Rh−C distance of 1.977(4) Å. The X-ray diffraction analysis of a red crystal revealed that it was a pseudo-merohedral twin resulting from the cocrystallization of 15 and 16, in the same unit cell, in an approximately 1:2 proportion. Although the results of the analysis are not enough accurate to permit a deep discussion of the structural parameters, they confirm the bond sequence in both 15 and 16 and therefore their formation.
The behavior of 3-(trifluoromethyl)quinoline points out that the introduction of an electron-withdrawing substituent at the heteroring allows the direct activation of the C−H bond at the elusive positions 6 and 7 of the heterocycle, although the selectivity of the activation is significantly reduced.

■ CONCLUDING REMARKS
This study reveals that complex RhH{κ 3 -P,O,P-[xant(P i Pr 2 ) 2 ]} promotes the C−H bond activation of quinoline and monosubstituted quinolines, to form square-planar rhodium(I)quinolinyl derivatives. Activation of the heteroring is preferred over activation of the carbocycle. Such selectivity could be related to some contribution of an anionic carbene resonance form to the rhodium−quinolinyl bond. The chemical shifts of the resonance corresponding to the metalated carbon, in a relatively low field, in the 13 C{ 1 H} NMR spectra seem to point out in this direction. Within the heteroring, the 3 position is always elusive, while it is possible to select between activation of 2 and 4 positions by the introduction of a methyl substituent at the appropriate place on the heterocycle, with the exception of the 8 position. The presence of an electron-withdrawing substituent such as trifluoromethyl at the 3 position of the heteroring allows us to activate the carbocycle at 6 and 7 positions, although the selectivity of the activation suffers a significant decrease.
In summary, the first systematic study on the transition metal-promoted C−H bond activation of substituted quinolines yielded clear patterns of behavior, which allow us to control the selectivity of the activation and to observe direct C−H bond activations of unprecedented positions. ■ EXPERIMENTAL SECTION General Information. All reactions were carried out with exclusion of air using Schlenk-tube techniques or in a drybox. Instrumental methods and X-ray details are given in the Supporting Information. In the NMR spectra ( Figures S2−S42), the chemical shifts (in ppm) are referenced to residual solvent peaks (    , and the resulting mixture was stirred at 80°C for 48 h. After this time, the solution was evaporated to dryness to afford a brown residue. Addition of pentane (4 mL) afforded an orange solid that was washed with pentane (2 × 2 mL) and dried in vacuo. Yield: 67 mg (26%). The reaction is quantitative, but the isolated yield is low due to its high solubility in pentane. The solid is extremely sensitive to air, preventing us from getting its elemental analysis. HRMS (electrospray, m/z): calcd for C 37 H 49 NOP 2
General information for the Experimental Section, structural analysis, and NMR spectra (PDF)